AU649543B2 - Composition and method of treating depigmentation disorders - Google Patents
Composition and method of treating depigmentation disorders Download PDFInfo
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- AU649543B2 AU649543B2 AU17854/92A AU1785492A AU649543B2 AU 649543 B2 AU649543 B2 AU 649543B2 AU 17854/92 A AU17854/92 A AU 17854/92A AU 1785492 A AU1785492 A AU 1785492A AU 649543 B2 AU649543 B2 AU 649543B2
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- pseudocatalase
- bicarbonate
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- 230000035614 depigmentation Effects 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims description 16
- 239000000203 mixture Substances 0.000 title claims description 16
- 108010036322 pseudocatalase Proteins 0.000 claims abstract description 30
- 230000000699 topical effect Effects 0.000 claims abstract description 15
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 4
- 150000003624 transition metals Chemical class 0.000 claims abstract description 4
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- SDPBZSAJSUJVAT-UHFFFAOYSA-N carbonic acid;manganese Chemical compound [Mn].OC(O)=O SDPBZSAJSUJVAT-UHFFFAOYSA-N 0.000 claims description 6
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910001424 calcium ion Inorganic materials 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical group OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 3
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 3
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 3
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- 239000011565 manganese chloride Substances 0.000 claims description 3
- 235000002867 manganese chloride Nutrition 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims description 2
- 230000000485 pigmenting effect Effects 0.000 claims 1
- 206010047642 Vitiligo Diseases 0.000 abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 208000035475 disorder Diseases 0.000 abstract description 11
- 208000012641 Pigmentation disease Diseases 0.000 abstract description 9
- 102000003425 Tyrosinase Human genes 0.000 abstract description 9
- 108060008724 Tyrosinase Proteins 0.000 abstract description 9
- 230000019612 pigmentation Effects 0.000 abstract description 9
- 206010015150 Erythema Diseases 0.000 abstract description 6
- 231100000321 erythema Toxicity 0.000 abstract description 6
- WMOSTDJFFWYKNF-UHFFFAOYSA-L hydrogen carbonate;manganese(2+) Chemical compound [Mn+2].OC([O-])=O.OC([O-])=O WMOSTDJFFWYKNF-UHFFFAOYSA-L 0.000 abstract description 3
- 210000003491 skin Anatomy 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- 239000006071 cream Substances 0.000 description 6
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 108010053835 Catalase Proteins 0.000 description 3
- 102000016938 Catalase Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000007323 disproportionation reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 208000006933 Hermanski-Pudlak Syndrome Diseases 0.000 description 2
- 206010071775 Hermansky-Pudlak syndrome Diseases 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical compound C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008309 hydrophilic cream Substances 0.000 description 2
- 210000002752 melanocyte Anatomy 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229960004469 methoxsalen Drugs 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OIALAIQRYISUEV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]e Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO OIALAIQRYISUEV-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- BUNGCZLFHHXKBX-UHFFFAOYSA-N 8-methoxypsoralen Natural products C1=CC(=O)OC2=C1C=C1CCOC1=C2OC BUNGCZLFHHXKBX-UHFFFAOYSA-N 0.000 description 1
- 208000002782 Acneiform Eruptions Diseases 0.000 description 1
- 241000197194 Bulla Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 206010012432 Dermatitis acneiform Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 101001077660 Homo sapiens Serine protease inhibitor Kazal-type 1 Proteins 0.000 description 1
- 101000606090 Homo sapiens Tyrosinase Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000006187 Onycholysis Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 102100025144 Serine protease inhibitor Kazal-type 1 Human genes 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010040829 Skin discolouration Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- PCWZKQSKUXXDDJ-UHFFFAOYSA-N Xanthotoxin Natural products COCc1c2OC(=O)C=Cc2cc3ccoc13 PCWZKQSKUXXDDJ-UHFFFAOYSA-N 0.000 description 1
- 208000003486 acatalasia Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 208000002352 blister Diseases 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000007854 depigmenting agent Substances 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 231100000040 eye damage Toxicity 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000002664 langerhans' cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 101150039067 maf-1 gene Proteins 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000008099 melanin synthesis Effects 0.000 description 1
- SQBBOVROCFXYBN-UHFFFAOYSA-N methoxypsoralen Natural products C1=C2OC(=O)C(OC)=CC2=CC2=C1OC=C2 SQBBOVROCFXYBN-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N p-hydroxybenzoic acid propyl ester Natural products CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002165 photosensitisation Effects 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- -1 propyl esters Chemical class 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002468 redox effect Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Transceivers (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
PCT No. PCT/GB92/00878 Sec. 371 Date Nov. 15, 1993 Sec. 102(e) Date Nov. 15, 1993 PCT Filed May 15, 1992 PCT Pub. No. WO92/20354 PCT Pub. Date Nov. 26, 1992.Vitiligo and other tyrosinase-positive depigmentation disorders are treated by topical application of a pseudocatalase and subsequent exposure to a sub-minimal erythema dose of UVB light. After a course of treatment, pigmentation of the affected areas can be maintained by treatment with the pseudocatalases without UVB light treatment. The preferred pseudocatalases are transition metal co-ordination complexes, especially manganese (II) bicarbonate.
Description
OPI DATE 30/12/92 APPLN. ID 17854/92 IIIl |ll llillllllllllll AOJP DATE 11/02/93 PCT NUMBER PCT/GB92/00878 11 II 11111111111111111111111 AU9217854 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/20354 A61K 33/24, 33/32, 33/34 Al A61K 33/26 (43) International Publication Date: 26 November 1992 (26.11.92) (21) International Application Number: PCT/GB92/00878 (81) Designated States: AT (European patent), AU, BE (European patent), CA, CH (European patent), CS, DE (Eu- (22) International Filing Date; 15 May 1992 (15.05.92) ropean patent), DK (European patent), ES (European patent), FI, FR (European patent), GB (European patent), GR (European patent), HU, IT (European patent), Priority data: JP, KR, LU (European patent), MC (European patent), 9110652.6 15 May 1991 (15.05.91) GB NL (European patent), NO, PL, RO, RU, SE (European patent), US.
Applicant (for all designated States except US): STIEFEL LABORATORIES, INC. [US/US]; 280-1 Ponee Lt Published *Bouleard Sut8 ral bs, FL 33136988 With international search report.
(72) Inventors; and Inventors/Applicants (for US only) WOOD, John, Martin 255 C/rc./e- [GB/DE]; SCHALLREUTER, Karin, Uta [DE/DE]; /ooo Feldbehnkehre 16, D-2085 Quickborn es Z 33/3 1 (74)Ageat: BURFORD, Anthony, Frederick; W.H. Beck, 5/ r I' .,cr Greener Co., 7 Stone Buildings, Lincoln's Inn, London WC2A 3SZ (GB).
4 649543 D OF T G T 0 D (54)Title: COMPOSITION AND METHOD OF TREATING DEPIGMENTATION DISORDERS lEFURE TREATMENT AFTER TREATMENT (37) Abstract Vitiligo and other tyrosinase-positive depigmentation disorders are treated by topical application of a pseudocatalase and subsequent exposure to a sub-minimal erythema dose of UVB light. After a course of treatment, pigmentation of the affected areas can be ma'itained by treatment with the pseudocatalase without UVB light treatment. The preferred pseudocatalases are transition metal co-ordination complexes, especially manganese (II) bicarbonate.
WO 92/20354 PCTT/B92/00878 -1- COMPOSITION AND METHOD OF TREATING DEPIGMENTATION DISORDERS The present invention relates to the treatment of tyrosinase-positive depigmentation disorders and has particular application to the treatment of vitiligo. It provides compositions for said treatment and methods of said treatment.
Vitiligo is a chronic depigmentation disorder in which the patient has unsightly white patches or spots which are caused by localized loss of pigment and are very liable to sunburn. Although the condition is not debilitating, it is often emotionally stressful to the patient. The cause presently is unknown but it has been speculated that it results from an autoimmune response, involvement of the nervous system or a toxic effect on melanocytes. Usually, the only treatment is the use of skin-colouring cosmetics to disguise the patches or, in the case of Blacks and Indians, of depigmenting agents such as hydroquinone to depigment the remaining pigmented skin. Some limited success in treatment has been reported using the so-called PUVA method.
In the PUVA method, methoxsalen (ie. 8-methoxy psoralen) or, less usually, other psoralens is administered orally and the patient subsequently exposed to UVA light.
Psoralens are plant extracts and have been known since ancient Egyptian times to act as photosensitizers. The psoralen is given systemically and hence the photosensitizing effect is not localized and, since this effect is in the UVA range (320-400 nm), the patient must wear special glasses during everyday life in order to prevent eye damage. Further, side effects of PUVA include nausea, erythema, oedema, dizziness, headache, WO 92/20354 PCTGB92/00878 -2vesiculation, bulla formation, onycholysis, acneiform eruption and severe skin pain. Long term risks include skin cancer, epidermal dystrophy, premature skin aging, cataract formation, and alterations in the immune system.
The treatment is believed to be toxic to normal lymphocytes and Langerhans' cells. Accordingly, the treatment usually is limited to elderly patients or to two years duration.
It has recently been proposed to mitigate some of the risks of PUVA by bathing the patient in a psoralen bath.
Other tyrosinase-positive depigmentation disorders include Hermansky-Pudlak Syndrome.
It has now surprisingly been found that vitiligo and other tyrosinase-positive depigmentation disorders can be effectively treated by exposing a patient to UVB light (290-320 nm) after topical application of manganese (II) bicarbonate or other pseudocatalase. Further, it has been found that, following pigmentation by said treatment, a level of pigmentation in affected areas can be retained, at least for a period of time, by topical application of the pseudocatalase without UVB exposure.
We have disclosed in a co-pending Patent Application of the same priority and filing dates and corresponding to UK Patent Application No. 9110651 that pseudocatalase can be used topically to enhance sun tanning.
By pseudocatalase, we mean a plasma membrane permeable physiologically acceptable compound which catalyzes the dismutation of H 2 0 2 in vivo in analogous manner to catalase.
Without wishing to be bound to any particular hypothesis, it is believed that vitiligo and other tyrosinase-positive depigmentation disorders are caused by a deficiency of catalase which permits a higher than normal -3peroxide ion concentration in melanocytes. Since tyrosinase is inactivated by peroxide ion, the tyrosinase-catalyzed oxidation of 1-tyrosine to 1-dopa required for melanin biosynthesis is inhibited. Further, since peroxide ion is photochemically reduced to hydroxyl ion, there is a concomitant increase in hydroxyl ion production.
Exposure of the skin to UVB radiation generates superoxide anion radicals which is a preferred substrate for human tyrosinase (40 times better than oxygen) thereby promoting melanin formation. However, the superoxide anion radicals are dismutated into dioxygen and peroxide ion causing an undesirable increase in hydroxyl ion concentration unless catalase or some other competing meohanism removes peroxide ion. Thus, the presence of a pseudocatalase is believed to allow sufficient UVB exposure for superoxide anion radical formation to promote pigmentation in catalase deficient areas without burning or other cell damage.
S 20 According to a first aspect of the present invention, there is provided a method for treating a tyrosinase-positive depigmentation disorder which comprises applying to at least the depigmented areas of the skin of a patient suffering therefrom an effective amount of a pseudocatalase and thereafter exposing the treated skin to UVB light to induce melanin formation in the depigmented areas.
In a second aspect, the invention provides a topical composition comprising a pseudocatalase and a physiologically 30 acceptable topical vehicle therefor. n* Nscf r0'0' ,Wid- 94032Zp:koper~dab.17854-9 -081,3 WO 92/20354 PCT/GB932/00878 -4of the skin of a patient sulffpei ng theprfron an ffectiv amount of a pseudocatalase and. er exposing the treated skin to U VB- to induce melanin formation in As mentioned previously, the invention has particular application to the treatment of vitiligo but can be applied to the treatment of other tyrosinase-positive depigmentation disorders, for example Hermansky-Pudlak Syndrome.
The pseudocatalase can be any physiologically acceptable compound which catalyzes the dismutation of hydrogen peroxide. Some compounds such as Mn(II) bicarbonate are already known to be pseudocatalases and others can be determined by simple screening tests.
The presently preferred pseudocatalases are transition metal co-ordination complexes in which the inductive effect of the electron acceptor ligand enhances the redox effect of the metal on hydrogen peroxide dismutation. Usually, the metal will be Cu(I), Fe(II) or, especially Mn(II) and the ligand will be bicarbonate. It is especially preferred that the pseudocatalase is Mn(II) bicarbonate complex.
Said complex readily can be prepared by contacting manganous chloride with excess bicarbonate in aqueous solution.
The pseudocatalase is formulated in a topical vehicle for use. Conveniently, the vehicle comprises a hydrophilic cream to which an aqueous solution or suspension of the pseudocatalase is added to form a cream or lotion.
Alternatively, the vehicle can be a bath oil although any other compatible topical vehicle can be used to provide a topical composition.
A. i r WO 92/20354 PCT/GB92/00878 Preferably, the composition contains calcium ions, suitably added as calcium chloride, to compensate for a calcium defect which appears to be present in vitiliginous skin. Usually, the calcium ion concentration will be 5 to 20 maF-1&- mki\> o\c The composition can contain components such as emollients, perfumes etc conventionally used in topical preparations.
Usually, the topical composition is applied twice a day to at least the depigmented areas of skin, usually to the entire skin surface After at least one of said applications, the patient is exposed to UVB light after a short delay, usually about 20 to 60 minutes, to allow for transport of the pseudocatalase into the epidermis. The UVB exposure is limited to prevent erythema and is increased over the period of treatment from a few seconds to about 5 minutes as the minimal erythema dose increases with UVB tolerance. The course of treatment is continued for several months until there is an acceptable level of pigmentation in the previously depigmented areas.
Thereafter, pigmentation is maintained by continuing daily application of the topical composition, possibly with reduced frequency, without UVB exposure. If and when pigment is lost from the affected areas, the exposure to UVB light is recommenced for as long as necessary to restore pigmentation.
The invention is illu:crated in the following nonlimiting Examples.
Example I Manganous chlor-ie (380 mg) was added to a solution of sodium bicarbonate g) in purified water (3.0 ml) at ,X D WO 92/20354 PCrGB92/00878 -6ambient temperature. The mixture was allowed to stand until the evolution of gas had ceased. The resultant pinkish brown liquid was mixed with a hydrophilic cream (100 g, Neribase) to provide a white cream.
Neribase is a cream vehicle containing Macrogol stearate 2000; stearic alcohol; liquid paraffin; white soft paraffin; polyacrylic acid; sodium hydroxide; disodium EDTA ethylenediaminetetraacetic acid disodium salt); methyl and propyl Paraben 4-hydroxybenzoic acid methyl and propyl esters); and water.
Example II The white cream of Example I was applied twice daily (morning and either afternoon or evening) to the depigmented areas (vitiligo spots) of several patients suffering from vitiligo. After about 20 minutes following one of said applications, the affected areas were exposed to UVB light for a short period of time to provide a subminimal erythema dose. As the patient's tolerance to UVB light increased, the exposure time was increased from a few seconds to a maximum of about 5 minutes. In all cases, the vitiligo spots were significantly pigmented after a course of treatment of between 3 and 6 months.
The accompanying Figures I and II show a typical improvement in the vitiligo patients treated. Both figures show the ear of the same patient. When the patient presented at the clinic, she had several large vitiligo spots including one in the region of the right ear (Fig.
After three months pseudocatalase/ UVB treatment as described above, many of the vitiligo spots had decreased substantially in size including the right ear spot (Fig.
II). Pseudocatalase/UVB treatment of this patient continued for a further three months, by which time there was a further substantial reduction in size of the vitiligo spots. The patient was then maintained with pseudocatalase treatment alone.
Example III The procedure of Example 1 was repeated using creams to which calcium chloride had been added to provide 5 millimolar calcium ion content. 18 patients were treated for a mean duration of 4.2 months; 14 of these patients had a partial res---nse and 2 showed a marked, although not complete, pi :ntation of vitiliginous skin areas.
Example IV The procedure of Example 1 was repeated using creams to which calcium chloride had been added to provide 10 millimolar calcium ion content. 12 patients were treated for a mean duration of 2.25 months; all had a partial response but none showed significant pigmentation of vitiliginous skin areas.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply thei inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
OS L o Z 94032,p:\operdab,1785492.81,7
Claims (10)
1. A method of pigmenting skin depigmented by a tyrosinase- positive depigmentation disorder which comprises applying to at least the depigmented areas of the skin an effective amount of a pseudocatalase and thereafter exposing the treated skin to UVB light to induce melanin formation in the depigmented areas.
2. A method as claimed in Claim 1, wherein the pseudocatalase is a transition metal co-ordination complex.
3. A method as claimed in Claim 2, wherein the pseudocatalase is a Cu(I), Fe(II) or Mn(II) co-ordination complex.
4. A method as claimed in Claim 3, wherein the ligand of said co-ordination complex is bicarbonate.
5. A method as claimed in Claim 4, wherein the pseudocatalase is a Mn(II)-bicarbonate complex.
6. A method as claimed in Claim 5, wherein the Mn(II)- bicarbonate complex has been obtained by contacting manganous chloride with excess sodium bicarbonate in aqueous solution.
7. A topical composition comprising a pseudocatalase selected from Cu(I), Fe(II) or Mn(II)-bicarbonate co- r ordination complexes and a physiologically acceptable topical 30 vehicle therefor. t
8. A composition as claimed in Claim 7, which contains 5 to 20 millimolar calcium ions.
9. A composition as claime Claim k7, herein the pseudocatalase is a Mn(II)-bicar onate impex.. 940322,p:\oper\dab,17854-92.081,8 L.i c -9- A composition as claimed in Claim 9, wherein the Mn(II)- bicarbonate complex has been obtained by contacting manganous chloride with excess sodium bicarbonate in aqueous solution.
11. Topical compositions or methods involving them, substantially as hereinbefore described with reference to the Examples and/or drawings. DATED this 23rd day of March, 1994. STIEFEL LABORATORIES, INC. By its Patent Attorneys DAVIES COLLISON CAVE r. 4 QI 94032Zp:\oper\dab,17854-92.081,9 Os S S
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9110652 | 1991-05-15 | ||
GB919110652A GB9110652D0 (en) | 1991-05-15 | 1991-05-15 | Composition and method of treating depigmentation disorders |
PCT/GB1992/000878 WO1992020354A1 (en) | 1991-05-15 | 1992-05-15 | Composition and method of treating depigmentation disorders |
Publications (2)
Publication Number | Publication Date |
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AU1785492A AU1785492A (en) | 1992-12-30 |
AU649543B2 true AU649543B2 (en) | 1994-05-26 |
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AU17854/92A Ceased AU649543B2 (en) | 1991-05-15 | 1992-05-15 | Composition and method of treating depigmentation disorders |
Country Status (20)
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US (1) | US5433942A (en) |
EP (1) | EP0584171B1 (en) |
JP (1) | JPH06510275A (en) |
KR (1) | KR100190978B1 (en) |
AT (1) | ATE183097T1 (en) |
AU (1) | AU649543B2 (en) |
CA (1) | CA2102514A1 (en) |
DE (1) | DE69229780T2 (en) |
ES (1) | ES2137185T3 (en) |
GB (1) | GB9110652D0 (en) |
GR (1) | GR3031483T3 (en) |
IE (1) | IE69854B1 (en) |
IL (1) | IL101871A (en) |
MY (1) | MY108848A (en) |
NZ (1) | NZ242748A (en) |
PH (1) | PH30792A (en) |
SG (1) | SG45381A1 (en) |
TW (1) | TW201695B (en) |
WO (1) | WO1992020354A1 (en) |
ZA (1) | ZA923561B (en) |
Families Citing this family (13)
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US6139850A (en) * | 1994-12-21 | 2000-10-31 | Cosmederm Technologies | Formulations and methods for reducing skin irritation |
WO1996019182A1 (en) * | 1994-12-21 | 1996-06-27 | Cosmederm Technologies | Formulations and methods for reducing skin irritation |
US7404967B2 (en) | 1994-12-21 | 2008-07-29 | Cosmederm, Inc. | Topical product formulations containing strontium for reducing skin irritation |
WO1996019183A1 (en) | 1994-12-21 | 1996-06-27 | Cosmederm Technologies | Formulations and methods for reducing skin irritation |
GB2307175A (en) * | 1995-11-14 | 1997-05-21 | Steifel Lab Inc | Topical composition comprising a transition metal and bicarbonate ions, particularly for the promotion of pigmentation |
US6979327B2 (en) * | 2000-02-25 | 2005-12-27 | Mount Sinai School Of Medicine | Treatment of vitiligo |
DE10043466A1 (en) * | 2000-09-04 | 2002-03-28 | Johannes Wohlrab | Non-irritating topical preparation for treating or preventing skin disorders, e.g. atopic dermatitis, psoriasis or aging symptoms, containing manganese salt to stimulate urea synthesis by keratinocytes |
FR2814945B1 (en) * | 2000-10-09 | 2003-02-14 | Oreal | CANITIY TREATMENT PROCESS |
US6630130B1 (en) | 2001-07-16 | 2003-10-07 | Pearl Grimes | Sunless tanning cream |
US20030224028A1 (en) * | 2002-05-13 | 2003-12-04 | Societe L'oreal S.A. | Metal complexes for promoting skin desquamation and/or stimulating epidermal renewal |
FR2839449B1 (en) * | 2002-05-13 | 2006-12-08 | Oreal | USE OF AT LEAST ONE METAL COMPLEX AS DESQUAMANT |
US20040148712A1 (en) | 2002-11-29 | 2004-08-05 | Francis Pruche | Composition for coloring a keratin material, comprising at least two components, and coloring processes |
JP4687436B2 (en) * | 2005-12-13 | 2011-05-25 | ウシオ電機株式会社 | Excimer light therapy device |
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LU71110A1 (en) * | 1974-10-15 | 1976-11-11 | ||
ZA786403B (en) * | 1977-12-01 | 1979-10-31 | Ici Australia Ltd | Process |
AU518946B2 (en) * | 1979-02-23 | 1981-10-29 | Kenneth John Hausler | Trace mineral (s) cream |
AU544544B2 (en) * | 1980-08-20 | 1985-06-06 | Erwin Gunther Walliczek | Cuprous complex for therapeutic use |
AU7552981A (en) * | 1980-12-08 | 1982-09-09 | Bio-Systems Research Inc. | Anti-viral, anti-bacterial and/or anti fungal composition containing metal oxyalkylate |
JPH0196107A (en) * | 1987-10-07 | 1989-04-14 | Kanebo Ltd | Skin cosmetic |
JPH02108612A (en) * | 1988-10-19 | 1990-04-20 | Shizen:Kk | Divalent and trivalent complex iron salt-compounded cosmetic |
EP0424033A3 (en) * | 1989-10-19 | 1991-07-31 | Pola Chemical Industries Inc | External skin preparation |
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1991
- 1991-05-15 GB GB919110652A patent/GB9110652D0/en active Pending
-
1992
- 1992-05-14 MY MYPI92000812A patent/MY108848A/en unknown
- 1992-05-14 IL IL10187192A patent/IL101871A/en not_active IP Right Cessation
- 1992-05-15 AT AT92910389T patent/ATE183097T1/en not_active IP Right Cessation
- 1992-05-15 EP EP92910389A patent/EP0584171B1/en not_active Expired - Lifetime
- 1992-05-15 DE DE69229780T patent/DE69229780T2/en not_active Expired - Fee Related
- 1992-05-15 WO PCT/GB1992/000878 patent/WO1992020354A1/en active IP Right Grant
- 1992-05-15 US US08/150,014 patent/US5433942A/en not_active Expired - Fee Related
- 1992-05-15 ES ES92910389T patent/ES2137185T3/en not_active Expired - Lifetime
- 1992-05-15 KR KR1019930703445A patent/KR100190978B1/en not_active IP Right Cessation
- 1992-05-15 AU AU17854/92A patent/AU649543B2/en not_active Ceased
- 1992-05-15 CA CA002102514A patent/CA2102514A1/en not_active Abandoned
- 1992-05-15 SG SG1996005300A patent/SG45381A1/en unknown
- 1992-05-15 ZA ZA923561A patent/ZA923561B/en unknown
- 1992-05-15 NZ NZ242748A patent/NZ242748A/en unknown
- 1992-05-15 JP JP4510487A patent/JPH06510275A/en active Pending
- 1992-05-15 PH PH44350A patent/PH30792A/en unknown
- 1992-06-04 TW TW081104408A patent/TW201695B/zh active
- 1992-07-01 IE IE921559A patent/IE69854B1/en not_active IP Right Cessation
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1999
- 1999-10-08 GR GR990402575T patent/GR3031483T3/en unknown
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JPH06510275A (en) | 1994-11-17 |
US5433942A (en) | 1995-07-18 |
NZ242748A (en) | 1995-01-27 |
MY108848A (en) | 1996-11-30 |
IL101871A (en) | 1997-01-10 |
DE69229780T2 (en) | 1999-12-16 |
IE921559A1 (en) | 1992-11-18 |
KR100190978B1 (en) | 1999-06-15 |
GB9110652D0 (en) | 1991-07-03 |
ZA923561B (en) | 1993-04-28 |
ES2137185T3 (en) | 1999-12-16 |
EP0584171B1 (en) | 1999-08-11 |
PH30792A (en) | 1997-10-17 |
CA2102514A1 (en) | 1992-11-16 |
EP0584171A1 (en) | 1994-03-02 |
ATE183097T1 (en) | 1999-08-15 |
TW201695B (en) | 1993-03-11 |
SG45381A1 (en) | 1998-01-16 |
IE69854B1 (en) | 1996-10-02 |
IL101871A0 (en) | 1992-12-30 |
GR3031483T3 (en) | 2000-01-31 |
AU1785492A (en) | 1992-12-30 |
WO1992020354A1 (en) | 1992-11-26 |
DE69229780D1 (en) | 1999-09-16 |
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